'Danger Signals' From Dying Cells Jolt Immune System Into Action

In 1994, Polly Matzinger came up with a controversial idea. The immunologist at the U.S. National Institute of Allergy and Infectious Diseases proposed that alarm signals released from injured and dying cells can kick our immune system into high gear even when no microbial threat is evident. Many of Matzinger's colleagues ridiculed her "danger hypothesis," and it has remained divisive ever since. But a new study lends strong support to the idea by identifying a new possible alarm molecule.

"I haven't read a paper with such strong data in a long time," says immunologist Yan Shi of the University of Calgary in Canada.

When you get the sniffles, your immune system detects the invasion of an adenovirus or other cold-causing pathogen and counterattacks. But what exactly sets off immune cells? They can definitely respond to the microbes' distinctive chemical signatures, so-called pathogen-associated molecular patterns, or PAMPs. But in some situations, such as autoimmune diseases and organ transplants, the immune system mobilizes even when no pathogen is evident, oddities that prompted Matzinger to propose her danger hypothesis. Researchers have nominated several possible danger signals, or alarmins, but many immunologists are skeptical that these compounds incite the immune system.

Now, viral immune biologist Daniel Pinschewer of the University of Geneva in Switzerland and colleagues provide evidence for a novel alarmin. The researchers found that in mice, infection with a particular virus triggers a surge in interleukin-33 (IL-33). This molecule helps the body fight off parasitic worms and abets asthma and allergic reactions. But it can also spill from dying cells, making it a good candidate for an alarmin.

To trace IL-33's effects, the team studied genetically altered mice that can't produce the molecule. They compared the number of cytotoxic T cells—which help battle a virus by killing body cells that harbor it—in normal mice and animals missing IL-33. The genetically altered mice carried 90% fewer cytotoxic T cells targeted against the virus than did normal animals, a deficiency that translated into a weaker immune counterattack. Although control mice evicted the virus, the IL-33-lacking animals often couldn't, the researchers report online today in Science.

Besides expanding the ranks of cytotoxic T cells, IL-33 seems to prime them for combat. IL-33 stimulates cells by latching on to a receptor protein on their surface called ST2. Cytotoxic T cells that carry ST2 were good fighters, as indicated by the lineup of defensive proteins they produced. By contrast, cells missing ST2 were wimpy, the researchers found.

Pinschewer and colleagues also tested whether the cells that emit IL-33 are in the right place in the body to influence cytotoxic T cells. They tracked the cells to the spleen, which serves as a staging area for immune cells. The virus that infects the mice presumably sports PAMPs that provoke immune cells. But by acting as an alarmin, IL-33 triggers a complementary reaction, Pinschewer says. "It is very important for driving the protective antiviral immune response."

Experts give the study high marks. Shi says he's enthusiastic about the possibility of using IL-33 to fight infections in patients. The study, he notes, "provides a pretty clear-cut path to potential clinical intervention."

That immune cells detect alarmins as well as PAMPs raises a question, says immunologist Joost Oppenheim of the National Cancer Institute in Frederick, Maryland. "We have so many defenses, what do we need more for?" He speculates that "the environment is so dirty" that we need multiple layers of protection.